US11174250B2ActiveUtilityA1
Substituted carboxamides as inhibitors of WDR5 protein-protein binding
Est. expiryMar 1, 2036(~9.6 yrs left)· nominal 20-yr term from priority
Inventors:Rima Al-AwarCarlos Armando Zepeda-VelazquezGennady PodaMethvin IsaacDavid UehlingBrian WilsonBabu JosephYong-Jun LiuPandiaraju SubramanianAhmed Mamai
C07D 235/08A61P 35/02C07D 405/12C07D 413/10C07D 237/14C07D 471/04C07D 237/24C07D 413/12C07D 491/08C07D 295/135C07D 401/14C07D 405/14A61P 35/00C07D 401/12C07D 235/24C07D 213/81C07D 213/82A61P 43/00A61K 45/06A61P 7/00
79
PatentIndex Score
3
Cited by
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References
23
Claims
Abstract
The present application is directed to compounds of Formula I:compositions comprising these compounds and their uses, for example as medicaments for the treatment of diseases, disorders or conditions mediated or treatable by inhibition of binding between WDR5 protein and its binding partners.
Claims
exact text as granted — not AI-modifiedThe invention claimed is:
1. A compound of Formula (I):
or a pharmaceutically acceptable salt thereof,
wherein:
A is F;
X 1 is CR 10 ;
X 2 is CR 10 ;
X 3 is CR 10 ;
X 4 is CR 10 ;
X 5 is CH;
X 6 is CH;
X 7 is CH;
R 1 is heterocycloalkyl, optionally substituted with one or more substituents independently selected from the group consisting of halo, C 1-6 alkyl, C 1-6 fluoroalkyl, C 1-6 alkylene-NR 5 R 6 , C 1-6 alkylene-OR 4 , C 1-6 alkylene-SR 4 , NR 5 R 6 , OR 4 , SR 4 , and C 3-10 cycloalkyl;
R 2 is selected from the group consisting of:
or a tautomer thereof;
R 4 is H, C 1-6 alkyl, C 1-6 fluoroalkyl, C(O)CH—, alkyl, or C(O)C 1-6 fluoroalkyl;
R 5 is H, C 1-6 alkyl, C 1-6 fluoroalkyl, C 1-6 alkylene-NH—C 1-6 alkyl, C 1-6 alkylene-N(C 1-6 alkyl)(C 1-6 alkyl), C 1-6 alkylene-O—C 1-6 alkyl, C 1-6 alkylene-C 3-6 cycloalkyl, C 1-6 alkylene-heterocycloalkyl, C 1-6 alkylene-C 6-10 aryl, C 1-6 alkylene-heteroaryl, C(O)C 1-6 alkyl, C(O)C 1-6 fluoroalkyl, C(O)NHC 1-6 alkyl, C(O)OC 1-6 alkyl, S(O) 2 C 1-6 alkyl, S(O) 2 NHC 1-6 alkyl, or heterocycloalkyl;
R 6 is H, C 1-6 alkyl, C 1-6 fluoroalkyl, C 1-6 alkylene-NH—C 1-6 alkyl, C 1-6 alkylene-N(C 1-6 alkyl)(C 1-6 alkyl), C 1-6 alkylene-O—C 1-6 alkyl, C 1-6 alkylene-C 3-6 cycloalkyl, C 1-6 alkylene-heterocycloalkyl, C 1-6 alkylene-C 6-10 aryl, C 1-6 alkylene-heteroaryl, C(O)C 1-6 alkyl, C(O)C 1-6 fluoroalkyl, C(O)NHC 1-6 alkyl, C(O)OC 1-6 alkyl, S(O) 2 C 1-6 alkyl, S(O) 2 NHC 1-6 alkyl, or heterocycloalkyl; or
R 5 and R 6 , together with the nitrogen atom to which they are attached, form a 3-10 membered heterocyclyl, optionally substituted with one or more substituents independently selected from the group consisting of halo, CN, C 1-6 alkyl, C 1-6 fluoroalkyl, C 1-6 alkylene-O—C 1-6 alkyl, C 1-6 alkylene-NH—C 1-6 alkyl, C 1-6 alkylene-N(C 1-6 alkyl)(C 1-6 alkyl),C 1-6 alkylene-C 3-6 cycloalkyl, C 1-6 alkylene-heterocycloalkyl, C 1-6 alkylene-C 6-10 aryl, C 1-6 alkylene-heteroaryl, C(O)C 1-6 alkyl, C(O)C 1-6 fluoroalkyl, C(O)NHC 1-6 alkyl, C(O)OC 1-6 alkyl, OH, OC 1-6 alkyl, OC 1-6 fluoroalkyl, S(O) 2 C 1-6 alkyl, and S(O) 2 NHC 1-6 alkyl;
R 7 is H, C 1-6 alkyl, C 1-6 fluoroalkyl, C(O)C 1-6 alkyl, or C(O)C 1-6 fluoroalkyl;
R 8 is H, C 1-6 alkyl, C 1-6 fluoroalkyl, C(O)C 1-6 alkyl, or C(O)C 1-6 fluoroalkyl;
R 9 is H, C 1-6 alkyl, C 1-6 fluoroalkyl, C(O)C 1-6 alkyl, or C(O)C 1-6 fluoroalkyl; or
R 8 and R 9 , together with the nitrogen atom to which they are attached, form a 3-10 membered heterocyclyl, optionally substituted with one or more substituents independently selected from the group consisting of halo, CN, C 1-6 alkyl, C 1-6 fluoroalkyl, OH, OC 1-6 alkyl, or OC 1-6 fluoroalkyl;
R 10 is H, halo, CN, C 1-6 alkyl, C 1-6 fluoroalkyl, C 1-6 alkylene-R 14 , C 1-6 alkylene-NR 12 R 13 , C 1-6 alkylene-OR 11 , C 1-6 alkylene-SR 11 , C(O)NR 12 R 13 , C(O)OR 11 , C(S)NR 12 R 13 , C(S)OR 11 , NR 12 R 13 , OR 11 , OC 1-6 alkylene-R 14 , OC 1-6 alkylene-NR 12 R 13 , OC 1-6 alkylene-OR 11 , OC 1-6 alkylene-SR 11 , SR 11 , SC 1-6 alkylene-R 14 , SC 1-6 alkylene-NR 12 R 13 , SC 1-6 alkylene-OR 11 , SC 1-6 alkylene-SR 11 , or R 14 ;
R 11 is H, C 1-6 alkyl, C 1-6 fluoroalkyl, C 1-6 alkylene-C 3-10 cycloalkyl, C 1-6 alkylene-heterocycloalkyl, C 1-6 alkylene-C 6-10 aryl, C 1-6 alkylene-heteroaryl, C(O)C 1-6 alkyl, C(O)C 1-6 fluoroalkyl, C 3-10 cycloalkyl, heterocycloalkyl, C 6-10 aryl, or heteroaryl, each optionally substituted with one or more substituents independently selected from the group consisting of halo, CN, C 1-6 alkyl, C 1-6 alkylene-NR 16 R 17 , C 1-6 alkylene-OR 15 , C 1-6 alkylene-SR 15 , C 1-6 alkylene-C 3-10 cycloalkyl, C 1-6 alkylene-C 6-10 aryl, C 1-6 alkylene-heterocycloalkyl, C 1-6 alkylene-heteroaryl, C 1-6 alkylene-R 15 , C(O)NR 16 R 17 , C(O)OR 15 , C(O)R 15 , NR 16 R 17 , OR 15 , SR 15 , S(O)C 1-6 alkyl, S(O) 2 C 1-6 alkyl, C 3-10 cycloalkyl, heterocycloalkyl, C 6-10 aryl, and heteroaryl;
R 12 is H, C 1-10 alkyl, C 1-10 fluoroalkyl, C 1-6 alkylene-C 3-10 cycloalkyl, C 1-6 alkylene-heterocycloalkyl, C 1-6 alkylene-C 6-10 aryl, C 1-6 alkylene-heteroaryl, C(O)C 1-6 alkyl, C(O)C 1-6 fluoroalkyl, C 3-10 cycloalkyl, heterocycloalkyl, C 6-10 aryl, or heteroaryl, each optionally substituted with one or more substituents independently selected from the group consisting of halo, CN, C 1-6 alkyl, C 1-6 alkylene-NR 16 R 17 , C 1-6 alkylene-OR 15 , C 1-6 alkylene-SR 15 , C 1-6 alkylene-C 3-10 cycloalkyl, C 1-6 alkylene-C 6-10 aryl, C 1-6 alkylene-heterocycloalkyl, C 1-6 alkylene-heteroaryl, C 1-6 alkylene-R 15 , C(O)NR 16 R 17 , C(O)OR 15 , C(O)R 15 , NR 16 R 17 , OR 15 , SR 15 , S(O)C 1-6 alkyl, S(O) 2 C 1-6 alkyl, C 3-10 cycloalkyl, heterocycloalkyl, C 6-10 aryl, and heteroaryl;
R 13 is H, C 1-10 alkyl, C 1-10 fluoroalkyl, C 1-6 alkylene-C 3-10 cycloalkyl, C 1-6 alkylene-heterocycloalkyl, C 1-6 alkylene-C 6-10 aryl, C 1-6 alkylene-heteroaryl, C(O)C 1-6 alkyl, C(O)C 1-6 fluoroalkyl, C 3-10 cycloalkyl, heterocycloalkyl, C 6-10 aryl, or heteroaryl, each optionally substituted with one or more substituents independently selected from the group consisting of halo, CN, C 1-6 alkyl, C 1-6 alkylene-NR 16 R 17 , C 1-6 alkylene-OR 15 , C 1-6 alkylene-SR 15 , C 1-6 alkylene-C 3-10 cycloalkyl, C 1-6 alkylene-C 6-10 aryl, C 1-6 alkylene-heterocycloalkyl, C 1-6 alkylene-heteroaryl, C 1-6 alkylene-R 15 , C(O)NR 16 R 17 , C(O)OR 15 , C(O)R 15 , NR 16 R 17 , OR 15 , SR 15 , S(O)C 1-6 alkyl, S(O) 2 C 1-6 alkyl, C 3-10 cycloalkyl, heterocycloalkyl, C 6-10 aryl, and heteroaryl; or
R 12 and R 13 , together with the nitrogen atom to which they are attached, form a 3-10 membered heterocyclyl, optionally substituted with one or more substituents independently selected from the group consisting of halo, CN, C 1-6 alkyl, C 1-6 alkylene-NR 16 R 17 , C 1-6 alkylene-OR 15 , C 1-6 alkylene-SR 15 , C 1-6 alkylene-C 3-10 cycloalkyl, C 1-6 alkylene-C 6-10 aryl, C 1-6 alkylene-heterocycloalkyl, C 1-6 alkylene-heteroaryl, C 1-6 alkylene-R 15 , C(O)NR 16 R 17 , C(O)OR 15 , C(O)R 15 , NR 16 R 17 , OR 15 , SR 15 , S(O)C 1-6 alkyl, S(O) 2 C 1-6 alkyl, C 3-10 cycloalkyl, heterocycloalkyl, C 6-10 aryl, and heteroaryl;
R 14 is C(O)C 1-6 alkyl, C(O)C 1-6 fluoroalkyl, C 3-10 cycloalkyl, heterocycloalkyl, C 6-10 aryl, or heteroaryl, each optionally substituted with one or more substituents independently selected from the group consisting of halo, CN, C 1-6 alkyl, C 1-6 alkylene-NR 16 R 17 , C 1-6 alkylene-OR 15 , C 1-6 alkylene-SR 15 , C 1-6 alkylene-C 3-10 cycloalkyl, C 1-6 alkylene-heterocycloalkyl, C 1-6 alkylene-C 6-10 aryl, C 1-6 alkylene-heteroaryl, C 1-6 alkylene-R 5 , C(O)R 15 , C(O)OR 5 , C(O)NR 16 R 17 , NR 16 R 17 , OR 15 , SR 15 , S(O)C 1-6 alkyl, S(O) 2 C 1-6 alkyl, C 3-10 cycloalkyl, heterocycloalkyl, C 6-10 aryl, and heteroaryl;
R 15 is H, C 1-6 alkyl, C 1-6 fluoroalkyl, C 1-6 alkylene-C 3-10 cycloalkyl, C 1-6 alkylene-heterocycloalkyl, C 1-6 alkylene-C 6-10 aryl, C(O)C 1-6 alkyl, C(O)C 1-6 fluoroalkyl, C 3-10 cycloalkyl, heterocycloalkyl, or C 6-10 aryl, each optionally substituted with one or more substituents independently selected from the group consisting of halo, CN, C 1-6 alkyl, C 1-6 fluoroalkyl, C 1-6 alkylene-NH 2 , C 1-6 alkylene-NHC 1-6 alkyl, C 1-6 alkylene-N(C 1-6 alkyl)(C 1-6 alkyl), C 1-6 alkylene-OH, C 1-6 alkylene-O—C 1-6 alkyl, C 1-6 alkylene-SH, C 1-6 alkylene-S—C 1-6 alkyl, C 1-6 alkylene-C 3-10 cycloalkyl, C 1-6 alkylene-heterocycloalkyl, C 1-6 alkylene-C 6-10 aryl, C 1-6 alkylene-heteroaryl, C(O)C 1-6 alkyl, C(O)C 1-6 fluoroalkyl, C(O)NH 2 , C(O)NHC 1-6 alkyl, C(O)N(C 1-6 alkyl)(C 1-6 alkyl), C(O)OH, C(O)OC 1-6 alkyl, NH 2 , NHC 1-6 alkyl, N(C 1-6 alkyl)(C 1-6 alkyl), OH, OC 1-6 alkyl, OC 1-6 fluoroalkyl, SH, SC 1-6 alkyl, SC 1-6 fluoroalkyl, S(O)C 1-6 alkyl, S(O) 2 C 1-6 alkyl, C 3-10 cycloalkyl, heterocycloalkyl, C 6-10 aryl, and heteroaryl;
R 16 is H, C 1-6 alkyl, C 1-6 fluoroalkyl, C 1-6 alkylene-C 3-10 cycloalkyl, C 1-6 alkylene-heterocycloalkyl, C 1-6 alkylene-C 6-10 aryl, C(O)C 1-6 alkyl, C 3-10 cycloalkyl, heterocycloalkyl, or C 6-10 aryl, each optionally substituted with one or more substituents independently selected from the group consisting of halo, CN, C 1-6 alkyl, C 1-6 fluoroalkyl, C 1-6 alkylene-NH 2 , C 1-6 alkylene-NHC 1-6 alkyl, C 1-6 alkylene-N(C 1-6 alkyl)(C 1-6 alkyl), C 1-6 alkylene-OH, C 1-6 alkylene-O—C 1-6 alkyl, C 1-6 alkylene-SH, C 1-6 alkylene-S—C 1-6 alkyl, C 1-6 alkylene-C 3-10 cycloalkyl, C 1-6 alkylene-heterocycloalkyl, C 1-6 alkylene-C 6-10 aryl, C 1-6 alkylene-heteroaryl, C(O)C 1-6 alkyl, C(O)C 1-6 fluoroalkyl, C(O)NH 2 , C(O)NHC 1-6 alkyl, C(O)N(C 1-6 alkyl)(C 1-6 alkyl), C(O)OH, C(O)OC 1-6 alkyl, NH 2 , NHC 1-6 alkyl, N(C 1-6 alkyl)(C 1-6 alkyl), OH, OC 1-6 alkyl, OC 1-6 fluoroalkyl, SH, SC 1-6 alkyl, SC 1-6 fluoroalkyl, S(O)C 1-6 alkyl, S(O) 2 C 1-6 alkyl, C 3-10 cycloalkyl, heterocycloalkyl, C 6-10 aryl, and heteroaryl; and
R 17 is H, C 1-6 alkyl, C 1-6 fluoroalkyl, C 1-6 alkylene-C 3-10 cycloalkyl, C 1-6 alkylene-heterocycloalkyl, C 1-6 alkylene-C 6-10 aryl, C(O)C 1-6 alkyl, C 3-10 cycloalkyl, heterocycloalkyl, or C 6-10 aryl, each optionally substituted with one or more substituents independently selected from the group consisting of halo, CN, C 1-6 alkyl, C 1-6 fluoroalkyl, C 1-6 alkylene-NH 2 , C 1-6 alkylene-NHC 1-6 alkyl, C 1-6 alkylene-N(C 1-6 alkyl)(C 1-6 alkyl), C 1-6 alkylene-OH, C 1-6 alkylene-O—C 1-6 alkyl, C 1-6 alkylene-SH, C 1-6 alkylene-S—C 1-6 alkyl, C 1-6 alkylene-C 3-10 cycloalkyl, C 1-6 alkylene-heterocycloalkyl, C 1-6 alkylene-C 6-10 aryl, C 1-6 alkylene-heteroaryl, C(O)C 1-6 alkyl, C(O)C 1-6 fluoroalkyl, C(O)NH 2 , C(O)NHC 1-6 alkyl, C(O)N(C 1-6 alkyl)(C 1-6 alkyl), C(O)OH, C(O)OC 1-6 alkyl, NH 2 , NHC 1-6 alkyl, N(C 1-6 alkyl)(C 1-6 alkyl), OH, OC 1-6 alkyl, OC 1-6 fluoroalkyl, SH, SC 1-6 alkyl, SC 1-6 fluoroalkyl, S(O)C 1-6 alkyl, S(O) 2 C 1-6 alkyl, C 3-10 cycloalkyl, heterocycloalkyl, C 6-10 aryl, and heteroaryl; or
R 16 and R 17 , together with the nitrogen atom to which they are attached, form a 3-10 membered heterocyclyl, optionally substituted with one or more substituents independently selected from the group consisting of halo, CN, C 1-6 alkyl, C 1-6 fluoroalkyl, C 1-6 alkylene-NH 2 , C 1-6 alkylene-NHC 1-6 alkyl, C 1-6 alkylene-N(C 1-6 alkyl)(C 1-6 alkyl), C 1-6 alkylene-OH, C 1-6 alkylene-O—C 1-6 alkyl, C 1-6 alkylene-SH, C 1-6 alkylene-S—C 1-6 alkyl, C 1-6 alkylene-C 3-10 cycloalkyl, C 1-6 alkylene-heterocycloalkyl, C 1-6 alkylene-C 6-10 aryl, C 1-6 alkylene-heteroaryl, C(O)C 1-6 alkyl, C(O)C 1-6 fluoroalkyl, C(O)NH 2 , C(O)NHC 1-6 alkyl, C(O)N(C 1-6 alkyl)(C 1-6 alkyl), C(O)OH, C(O)OC 1-6 alkyl, NH 2 , NHC 1-6 alkyl, N(C 1-6 alkyl)(C 1-6 alkyl), OH, OC 1-6 alkyl, OC 1-6 fluoroalkyl, SH, SC 1-6 alkyl, SC 1-6 fluoroalkyl, S(O)C 1-6 alkyl, S(O) 2 C 1-6 alkyl, C 3-10 cycloalkyl, heterocycloalkyl, C 6-10 aryl, and heteroaryl;
with the proviso that:
(1) R 1 comprises at least one basic nitrogen atom; and
(2) all alkyl and alkylene groups not otherwise specified are optionally substituted with fluoro.
2. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein:
X 1 is CH;
X 2 is CH;
X 3 is CH; and
X 4 is CH.
3. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein:
X 5 is CH;
X 6 is CH; and
X 7 is CH.
4. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein R 1 is heterocycloalkyl, optionally substituted with one, two, or three substituents independently selected from the group consisting of halo, C 1-6 alkyl, C 1-6 fluoroalkyl, C 1-6 alkylene-NR 5 R 6 , C 1-6 alkylene-OR 4 , and NR 5 R 6 .
5. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein R 1 is selected from the group consisting of:
6. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein R 2 is selected from the group consisting of:
or a tautomer thereof.
7. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein R 4 is H, C 1-6 alkyl, or C(O)C 1-6 alkyl.
8. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein R 5 is H, C 1-6 alkyl, or heterocycloalkyl; and
R 6 is H, C 1-6 alkyl, or heterocycloalkyl.
9. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein R 5 and R 6 , together with the nitrogen atom to which they are attached, form a 3-10 membered heterocyclyl, optionally substituted with one, two, or three substituents independently selected from the group consisting of halo and C 1-6 alkyl.
10. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein R 7 is H or C 1-6 alkyl.
11. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein R 10 is H, halo, CN, C 1-6 alkyl, C 1-6 fluoroalkyl, C 1-6 alkylene-R 14 , C 1-6 alkylene-NR 12 R 13 , C 1-6 alkylene-OR 11 , C(O)NR 12 R 13 , C(O)OR 11 , NR 12 R 13 , OR 11 , OC 1-6 alkylene-R 14 , OC 1-6 alkylene-NR 12 R 13 , OC 1-6 alkylene-OR 11 , or R 14 .
12. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein R 11 is H, C 1-6 alkyl, C 1-6 fluoroalkyl, C 3-10 cycloalkyl, heterocycloalkyl, C 6-10 aryl, or heteroaryl.
13. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein:
R 12 is H, C 1-10 alkyl, C 1-10 fluoroalkyl, C 1-6 alkylene-C 3-10 cycloalkyl, C 1-6 alkylene-heterocycloalkyl, C 1-6 alkylene-C 6-10 aryl, C 1-6 alkylene-heteroaryl, C(O)C 1-6 alkyl, C(O)C 1-6 fluoroalkyl, C 3-10 cycloalkyl, heterocycloalkyl, C 6-10 aryl, or heteroaryl, each optionally substituted with one or more substituents independently selected from the group consisting of halo and C 1-6 alkyl; and
R 13 is H, C 1-10 alkyl, C 1-10 fluoroalkyl, C 1-6 alkylene-C 3-10 cycloalkyl, C 1-6 alkylene-heterocycloalkyl, C 1-6 alkylene-C 6-10 aryl, C 1-6 alkylene-heteroaryl, C(O)C 1-6 alkyl, C(O)C 1-6 fluoroalkyl, C 3-10 cycloalkyl, heterocycloalkyl, C 6-10 aryl, or heteroaryl, each optionally substituted with one or more substituents independently selected from the group consisting of halo and C 1-6 alkyl.
14. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein R 12 and R 13 , together with the nitrogen atom to which they are attached, form a 3-10 membered heterocyclyl, optionally substituted with one or more substituents independently selected from the group consisting of halo, C 1-6 alkyl, C 1-6 alkylene-C 3-10 cycloalkyl, C 1-6 alkylene-R 15 , NR 16 R 17 , OR 15 , S(O) 2 C 1-6 alkyl, and heterocycloalkyl.
15. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein R 14 is C 3-10 cycloalkyl or heterocycloalkyl.
16. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein R 15 is H, C 1-6 alkylene-C 6-10 aryl, or C 6-10 aryl, wherein C 1-6 alkylene-C 6-10 aryl and C 6-10 aryl are each optionally substituted with one or more substituents independently selected from the group consisting of halo and C 1-6 alkyl.
17. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein:
R 16 is H, C 1-6 alkyl, C 1-6 fluoroalkyl, C 1-6 alkylene-C 3-10 cycloalkyl, C 1-6 alkylene-heterocycloalkyl, C 1-6 alkylene-C 6-10 aryl, C 3-10 cycloalkyl, heterocycloalkyl, or C 6-10 aryl; and
R 17 is H, C 1-6 alkyl, C 1-6 fluoroalkyl, C 1-6 alkylene-C 3-10 cycloalkyl, C 1-6 alkylene-heterocycloalkyl, C 1-6 alkylene-C 6-10 aryl, C 3-10 cycloalkyl, heterocycloalkyl, or C 6-10 aryl.
18. The compound of claim 1 , wherein the compound is selected from the group consisting of:
N-[5-[5-[[(2S,6R)-2,6-dimethylmorpholin-4-yl]methyl]-2-fluorophenyl]-2-(4-methylpiperazin-1-yl)phenyl]-6-oxo-4-(trifluoromethyl)-1H-pyridine-3-carboxamide;
N-[5-[2-fluoro-5-(morpholin-4-ylmethyl)phenyl]-2-(4-methylpiperazin-1-yl)phenyl]-6-oxo-4-(trifluoromethyl)-1H-pyridine-3-carboxamide;
N-[5-[2-fluoro-4-(methoxymethoxy)-5-(2,4,4-trimethylpentan-2-ylcarbamoyl)phenyl]-2-(4-methylpiperazin-1-yl)phenyl]-6-oxo-4-(trifluoromethyl)-1H-pyridine-3-carboxamide;
N-[5-(5-carbamoyl-2-fluoro-4-hydroxyphenyl)-2-(4-methylpiperazin-1-yl)phenyl]-6-oxo-4-(trifluoromethyl)-1H-pyridine-3-carboxamide;
N-[5-[2-fluoro-5-(trifluoromethoxy)phenyl]-2-(4-methylpiperazin-1-yl)phenyl]-6-oxo-4-(trifluoromethyl)-1H-pyridine-3-carboxamide;
N-[5-[2-fluoro-5-(2-methylpropoxy)phenyl]-2-(4-methylpiperazin-1-yl)phenyl]-6-oxo-4-(trifluoromethyl)-1H-pyridine-3-carboxamide;
N-[5-[5-[(cyclohexylamino)methyl]-2-fluorophenyl]-2-(4-methylpiperazin-1-yl)phenyl]-6-oxo-4-(trifluoromethyl)-1H-pyridine-3-carboxamide;
N-[5-[2-fluoro-5-(morpholin-4-ylmethyl)phenyl]-2-(4-methylpiperazin-1-yl)phenyl]-6-oxo-1H-pyridazine-3-carboxamide;
N-[5-[2-fluoro-5-(morpholin-4-ylmethyl)phenyl]-2-(4-methylpiperazin-1-yl)phenyl]-3-methoxybenzamide;
4-fluoro-N-[5-[2-fluoro-5-(morpholin-4-ylmethyl)phenyl]-2-(4-methylpiperazin-1-yl)phenyl]-3,5-dimethylbenzamide;
N-[5-[2-fluoro-5-(morpholin-4-ylmethyl)phenyl]-2-(4-methylpiperazin-1-yl)phenyl]-1-methyl-6-oxo-4-(trifluoromethyl)pyridine-3-carboxamide;
methyl 4-fluoro-3-[4-(4-methylpiperazin-1-yl)-3-[[6-oxo-4-(trifluoromethyl)-1H-pyridine-3-carbonyl]-amino]phenyl]benzoate;
N-[5-[5-[(cyclopropylamino)methyl]-2-fluorophenyl]-2-(4-methylpiperazin-1-yl)phenyl]-6-oxo-4-(trifluoromethyl)-1H-pyridine-3-carboxamide;
N-[5-[5-[(cyclohexylamino)methyl]-2-fluorophenyl]-2-(4-methylpiperazin-1-yl)phenyl]-4-fluoro-3,5-dimethylbenzamide;
N-[5-[2-fluoro-5-(morpholin-4-ylmethyl)phenyl]-2-(4-methylpiperazin-1-yl)phenyl]-6-oxo-4-(trifluoromethyl)-1H-pyridazine-3-carboxamide;
N-[5-[5-(cyclopropylmethoxy)-2,4-difluorophenyl]-2-(4-methylpiperazin-1-yl)phenyl]-6-oxo-4-(trifluoromethyl)-1H-pyridine-3-carboxamide;
N-[5-[2-fluoro-3-(morpholin-4-ylmethyl)phenyl]-2-(4-methylpiperazin-1-yl)phenyl]-6-oxo-4-(trifluoromethyl)-1H-pyridine-3-carboxamide;
N-[5-[2-fluoro-5-(morpholin-4-ylmethyl)phenyl]-2-(4-methylpiperazin-1-yl)phenyl]-3-methylbenzamide;
N-[5-(2-fluorophenyl)-2-(4-methylpiperazin-1-yl)phenyl]-6-oxo-4-(trifluoromethyl)-1H-pyridine-3-carboxamide;
N-[2-(3,4-dimethylpiperazin-1-yl)-5-[2-fluoro-5-(morpholin-4-ylmethyl)phenyl]phenyl]-6-hydroxy-4-(trifluoromethyl)pyridine-3-carboxamide;
N-(2′-fluoro-5′-(morpholinomethyl)-4-((3S,5R)-3,4,5-trimethylpiperazin-1-yl)-[1,1′-biphenyl]-3-yl)-6-oxo-4-(trifluoromethyl)-1,6-dihydropyridine-3-carboxamide;
N-[2-[(2S)-2,4-dimethylpiperazin-1-yl]-5-[2-fluoro-5-(morpholin-4-ylmethyl)phenyl]phenyl]-6-oxo-4-(trifluoromethyl)-1H-pyridine-3-carboxamide;
N-[5-[2-fluoro-5-(morpholin-4-ylmethyl)phenyl]-2-(4-methylpiperazin-1-yl)phenyl]-4-methyl-6-oxo-1H-pyridine-3-carboxamide;
N-(2′,6-difluoro-4-(4-methylpiperazin-1-yl)-5′-(morpholinomethyl)-[1,1′-biphenyl]-3-yl)-6-oxo-4-(trifluoromethyl)-1,6-dihydropyridine-3-carboxamide;
N-[5-[5-(cyclohexylcarbamoyl)-2-fluorophenyl]-2-(4-methylpiperazin-1-yl)phenyl]-6-oxo-4-(trifluoromethyl)-1H-pyridine-3-carboxamide;
N-[5-[4-[(cyclopentylamino)methyl]-2-fluorophenyl]-2-(4-methylpiperazin-1-yl)phenyl]-6-oxo-4-(trifluoromethyl)-1H-pyridine-3-carboxamide;
N-[5-[4-[(cyclohexylamino)methyl]-2-fluorophenyl]-2-(4-methylpiperazin-1-yl)phenyl]-6-oxo-4-(trifluoromethyl)-1H-pyridine-3-carboxamide;
N-[5-[5-[(tert-butylamino)methyl]-2-fluorophenyl]-2-(4-methylpiperazin-1-yl)phenyl]-6-oxo-4-(trifluoromethyl)-1H-pyridine-3-carboxamide;
4-fluoro-N-[5-[2-fluoro-5-(morpholin-4-ylmethyl)phenyl]-2-(4-methylpiperazin-1-yl)phenyl]-3-methylbenzamide;
N-[5-[2-fluoro-5-[(oxan-4-ylamino)methyl]phenyl]-2-(4-methylpiperazin-1-yl)phenyl]-6-oxo-4-(trifluoromethyl)-1H-pyridine-3-carboxamide;
N-[5-[2-fluoro-4-(morpholin-4-ylmethyl)phenyl]-2-(4-methylpiperazin-1-yl)phenyl]-6-oxo-4-(trifluoromethyl)-1H-pyridine-3-carboxamide;
N-[5-[5-[(dimethylamino)methyl]-2-fluorophenyl]-2-(4-methylpiperazin-1-yl)phenyl]-6-oxo-4-(trifluoromethyl)-1H-pyridine-3-carboxamide;
4-fluoro-N-[5-[2-fluoro-5-(morpholin-4-ylmethyl)phenyl]-2-(4-methylpiperazin-1-yl)phenyl]-3-methyl-5-(trifluoromethyl)benzamide;
N-[5-[5-[[(4,4-difluorocyclohexyl)amino]methyl]-2-fluorophenyl]-2-(4-methylpiperazin-1-yl)phenyl]-6-oxo-4-(trifluoromethyl)-1H-pyridine-3-carboxamide;
N-[5-[2-fluoro-5-[[methyl(oxetan-3-yl)amino]methyl]phenyl]-2-(4-methylpiperazin-1-yl)phenyl]-6-oxo-4-(trifluoromethyl)-1H-pyridine-3-carboxamide;
N-[5-[2-fluoro-5-(morpholin-4-ylmethyl)phenyl]-2-(4-methylpiperazin-1-yl)phenyl]-4-hydroxy-2-(trifluoromethyl)benzamide;
N-[5-[5-[(cyclohexylamino)methyl]-2-fluorophenyl]-2-[(3R,5S)-3,4,5-trimethylpiperazin-1-yl]phenyl]-6-oxo-4-(trifluoromethyl)-1H-pyridine-3-carboxamide;
N-[5-[5-(cyclohexylcarbamoyl)-2-fluorophenyl]-2-[(3R,5S)-3,4,5-trimethylpiperazin-1-yl]phenyl]-6-oxo-4-(trifluoromethyl)-1H-pyridine-3-carboxamide;
N-[5-[2-fluoro-5-(morpholine-4-carbonyl)phenyl]-2-[(3R,5S)-3,4,5-trimethylpiperazin-1-yl]phenyl]-6-oxo-4-(trifluoromethyl)-1H-pyridine-3-carboxamide;
2,3-difluoro-N-[5-[2-fluoro-5-(morpholin-4-ylmethyl)phenyl]-2-(4-methylpiperazin-1-yl)phenyl]-5-hydroxybenzamide;
4-(difluoromethyl)-N-[5-[2-fluoro-5-(morpholin-4-ylmethyl)phenyl]-2-(4-methylpiperazin-1-yl)phenyl]-6-oxo-1H-pyridine-3-carboxamide;
(R)—N-(2′-fluoro-5′-((3-hydroxypyrrolidin-1-yl)methyl)-4-(4-methylpiperazin-1-yl)-[1,1′-biphenyl]-3-yl)-6-methoxy-4-(trifluoromethyl)nicotinamide;
N-[5-[2-fluoro-5-[(4-morpholin-4-ylpiperidin-1-yl)methyl]phenyl]-2-(4-methylpiperazin-1-yl)phenyl]-6-methoxy-4-(trifluoromethyl)pyridine-3-carboxamide;
N-[5-[2-fluoro-5-[[(3S)-3-propan-2-ylpyrrolidin-1-yl]methyl]phenyl]-2-(4-methylpiperazin-1-yl)phenyl]-6-methoxy-4-(trifluoromethyl)pyridine-3-carboxamide;
N-[5-[5-[(4-acetylpiperazin-1-yl)methyl]-2-fluorophenyl]-2-(4-methylpiperazin-1-yl)phenyl]-6-methoxy-4-(trifluoromethyl)pyridine-3-carboxamide;
N-[5-[2-fluoro-5-[(4-fluoropiperidin-1-yl)methyl]phenyl]-2-(4-methylpiperazin-1-yl)phenyl]-6-methoxy-4-(trifluoromethyl)pyridine-3-carboxamide;
N-[5-[2-fluoro-5-(3-oxa-6-azabicyclo[3.1.1]heptan-6-ylmethyl)phenyl]-2-(4-methylpiperazin-1-yl)phenyl]-6-methoxy-4-(trifluoromethyl)pyridine-3-carboxamide;
(R)—N-(2′-fluoro-4-(4-methylpiperazin-1-yl)-5′-((3-(methylsulfonyl)pyrrolidin-1-yl)methyl)-[1,1′-biphenyl]-3-yl)-6-methoxy-4-(trifluoromethyl)nicotinamide;
(S)—N-(2′-fluoro-5′-((methyl(tetrahydrofuran-3-yl)amino)methyl)-4-(4-methylpiperazin-1-yl)-[1,1′-biphenyl]-3-yl)-6-methoxy-4-(trifluoromethyl)nicotinamide;
N-[5-[5-[(2,2-dimethylmorpholin-4-yl)methyl]-2-fluorophenyl]-2-(4-methylpiperazin-1-yl)phenyl]-6-methoxy-4-(trifluoromethyl)pyridine-3-carboxamide;
N-[2-(4-ethylpiperazin-1-yl)-5-[2-fluoro-5-(morpholin-4-ylmethyl)phenyl]phenyl]-6-oxo-4-(trifluoromethyl)-1H-pyridine-3-carboxamide;
N-[5-[5-[(cyclohexylamino)methyl]-2-fluorophenyl]-2-(4-ethylpiperazin-1-yl)phenyl]-6-oxo-4-(trifluoromethyl)-1H-pyridine-3-carboxamide;
[4-[4-[2-fluoro-5-(morpholin-4-ylmethyl)phenyl]-2-[[6-oxo-4-(trifluoromethyl)-1H-pyridine-3-carbonyl]amino]phenyl]-1-methylpiperazin-2-yl]methyl 2,2-dimethylpropanoate;
N-[5-[2-fluoro-5-(morpholin-4-ylmethyl)phenyl]-2-[3-(hydroxymethyl)-4-methylpiperazin-1-yl]phenyl]-6-oxo-4-(trifluoromethyl)-1H-pyridine-3-carboxamide;
N-[5-[5-[[4-(cyclopropylmethyl)piperazin-1-yl]methyl]-2-fluorophenyl]-2-(4-methylpiperazin-1-yl)phenyl]-6-oxo-4-(trifluoromethyl)-1H-pyridine-3-carboxamide;
N-[5-[5-[[cyclohexyl(methyl)amino]methyl]-2-fluorophenyl]-2-(4-methylpiperazin-1-yl)phenyl]-6-oxo-4-(trifluoromethyl)-1H-pyridine-3-carboxamide;
N-[5-[2-fluoro-5-[[4-[(4-fluorophenyl)methyl]piperazin-1-yl]methyl]phenyl]-2-(4-methylpiperazin-1-yl)phenyl]-6-oxo-4-(trifluoromethyl)-1H-pyridine-3-carboxamide;
(R)—N-(2′-fluoro-5′-((3-hydroxypyrrolidin-1-yl)methyl)-4-(4-methylpiperazin-1-yl)-[1,1′-biphenyl]-3-yl)-6-oxo-4-(trifluoromethyl)-1,6-dihydropyridine-3-carboxamide;
N-[5-[2-fluoro-5-[(4-morpholin-4-ylpiperidin-1-yl)methyl]phenyl]-2-(4-methylpiperazin-1-yl)phenyl]-6-oxo-4-(trifluoromethyl)-1H-pyridine-3-carboxamide;
(R)—N-(5′-((3-(dimethylamino)pyrrolidin-1-yl)methyl)-2′-fluoro-4-(4-methylpiperazin-1-yl)-[1,1′-biphenyl]-3-yl)-6-oxo-4-(trifluoromethyl)-1,6-dihydropyridine-3-carboxamide;
N-[5-[2-fluoro-5-(piperazin-1-ylmethyl)phenyl]-2-(4-methylpiperazin-1-yl)phenyl]-6-oxo-4-(trifluoromethyl)-1H-pyridine-3-carboxamide;
N-[5-[2-fluoro-5-[(4-fluoropiperidin-1-yl)methyl]phenyl]-2-(4-methylpiperazin-1-yl)phenyl]-6-oxo-4-(trifluoromethyl)-1H-pyridine-3-carboxamide;
N-[5-[2-fluoro-5-(3-oxa-6-azabicyclo[3.1.1]heptan-6-ylmethyl)phenyl]-2-(4-methylpiperazin-1-yl)phenyl]-6-oxo-4-(trifluoromethyl)-1H-pyridine-3-carboxamide;
N-[5-[2-fluoro-5-[[(3R)-3-methylsulfonylpyrrolidin-1-yl]methyl]phenyl]-2-(4-methylpiperazin-1-yl)phenyl]-6-oxo-4-(trifluoromethyl)-1H-pyridine-3-carboxamide;
(S)—N-(2′-fluoro-5′-((methyl(tetrahydrofuran-3-yl)amino)methyl)-4-(4-methylpiperazin-1-yl)-[1,1′-biphenyl]-3-yl)-6-oxo-4-(trifluoromethyl)-1,6-dihydropyridine-3-carboxamide;
N-[5-[5-[(2,2-dimethylmorpholin-4-yl)methyl]-2-fluorophenyl]-2-(4-methylpiperazin-1-yl)phenyl]-6-oxo-4-(trifluoromethyl)-1H-pyridine-3-carboxamide;
N-[5-(3-cyano-2,6-difluorophenyl)-2-[(3R,5S)-3,4,5-trimethylpiperazin-1-yl]phenyl]-6-oxo-4-(trifluoromethyl)-1H-pyridine-3-carboxamide;
N-[5-[5-[(cyclohexylamino)methyl]-2,4-difluorophenyl]-2-[(3S,5R)-3,4,5-trimethylpiperazin-1-yl]phenyl]-6-oxo-4-(trifluoromethyl)-1H-pyridine-3-carboxamide;
N-[5-[2-fluoro-5-(phenylcarbamoyl)phenyl]-2-[(3R,5S)-3,4,5-trimethylpiperazin-1-yl]phenyl]-6-oxo-4-(trifluoromethyl)-1H-pyridine-3-carboxamide;
N-(5′-(cyclohexylcarbamoyl)-4-(3,4-dimethylpiperazin-1-yl)-2′-fluoro-[1,1′-biphenyl]-3-yl)-6-oxo-4-(trifluoromethyl)-1,6-dihydropyridine-3-carboxamide;
N-[5-[3-[(cyclohexylamino)methyl]-2,4-difluorophenyl]-2-[(3S,5R)-3,4,5-trimethylpiperazin-1-yl]phenyl]-6-oxo-4-(trifluoromethyl)-1H-pyridine-3-carboxamide;
N-(4-(3-(dimethylamino)pyrrolidin-1-yl)-2′-fluoro-5′-(morpholinomethyl)-[1,1′-biphenyl]-3-yl)-6-oxo-4-(trifluoromethyl)-1,6-dihydropyridine-3-carboxamide;
N-(2′-fluoro-4-(4-methyl-1,4-diazepan-1-yl)-5′-(morpholinomethyl)-[1,1′-biphenyl]-3-yl)-6-oxo-4-(trifluoromethyl)-1,6-dihydropyridine-3-carboxamide;
N-(2′-fluoro-4-(4-methyl-1,4-diazepan-1-yl)-5′-(morpholinomethyl)-[1,1′-biphenyl]-3-yl)-1-methyl-6-oxo-4-(trifluoromethyl)-1,6-dihydropyridine-3-carboxamide;
N-[5-[2-fluoro-5-(methylcarbamoyl)phenyl]-2-[(3R,5S)-3,4,5-trimethylpiperazin-1-yl]phenyl]-6-oxo-4-(trifluoromethyl)-1H-pyridine-3-carboxamide;
N-[2-[3-(dimethylamino)pyrrolidin-1-yl]-5-[2-fluoro-5-(morpholin-4-ylmethyl)phenyl]phenyl]-4-fluoro-3,5-dimethylbenzamide;
4-fluoro-N-[5-[2-fluoro-5-(morpholin-4-ylmethyl)phenyl]-2-(4-methyl-1,4-diazepan-1-yl)phenyl]-3,5-dimethylbenzamide;
N-[5-[5-(cyclopropylcarbamoyl)-2-fluorophenyl]-2-[(3R,5S)-3,4,5-trimethylpiperazin-1-yl]phenyl]-6-oxo-4-(trifluoromethyl)-1H-pyridine-3-carboxamide;
4-fluoro-N-[5-[2-fluoro-5-(morpholin-4-ylmethyl)phenyl]-2-(2-methyl-1,3,3a,4,6,6a-hexahydropyrrolo[3,4-c]pyrrol-5-yl)phenyl]-3,5-dimethylbenzamide;
4-fluoro-N-[5-[2-fluoro-5-(morpholin-4-ylmethyl)phenyl]-2-[4-(2,2,2-trifluoroethyl)piperazin-1-yl]phenyl]-3,5-dimethylbenzamide;
N-[5-[2-fluoro-5-(morpholin-4-ylmethyl)phenyl]-2-[4-(2,2,2-trifluoroethyl)piperazin-1-yl]phenyl]-6-oxo-4-(trifluoromethyl)-1H-pyridine-3-carboxamide;
N-(2′,5-difluoro-4-(4-methylpiperazin-1-yl)-5′-(morpholinomethyl)-[1,1′-biphenyl]-3-yl)-6-oxo-4-(trifluoromethyl)-1,6-dihydropyridine-3-carboxamide;
N-(2,2′-difluoro-4-(4-methylpiperazin-1-yl)-5′-(morpholinomethyl)-[1,1′-biphenyl]-3-yl)-6-oxo-4-(trifluoromethyl)-1,6-dihydropyridine-3-carboxamide;
N-[5-[2-fluoro-5-(morpholin-4-ylmethyl)phenyl]-2-(2-methyl-1,3,3a,4,6,6a-hexahydropyrrolo[3,4-c]pyrrol-5-yl)phenyl]-6-oxo-4-(trifluoromethyl)-1H-pyridine-3-carboxamide;
N-[2-[3-(dimethylamino)pyrrolidin-1-yl]-5-[2-fluoro-5-(morpholin-4-ylmethyl)phenyl]phenyl]-1-methyl-6-oxo-4-(trifluoromethyl)pyridine-3-carboxamide;
N-[5-[2-fluoro-5-(morpholin-4-ylmethyl)phenyl]-2-[(2R)-2,4-dimethylpiperazin-1-yl]phenyl]-6-oxo-4-(trifluoromethyl)-1H-pyridine-3-carboxamide;
N-[5-[2-fluoro-5-(morpholin-4-ylmethyl)phenyl]-2-(4-methylpiperazin-1-yl)phenyl]-6-oxo-1H-pyridine-3-carboxamide;
6-acetamido-N-[5-[2-fluoro-5-(morpholin-4-ylmethyl)phenyl]-2-(4-methylpiperazin-1-yl)phenyl]-4-methylpyridine-3-carboxamide;
N-[5-[5-[[4-(cyclopropylmethyl)piperazin-1-yl]methyl]-2-fluorophenyl]-2-(4-methylpiperazin-1-yl)phenyl]-6-methoxy-4-(trifluoromethyl)pyridine-3-carboxamide;
N-[5-[5-[cyclohexyl(methyl)carbamoyl]-2-fluorophenyl]-2-(4-methylpiperazin-1-yl)phenyl]-6-oxo-4-(trifluoromethyl)-1H-pyridine-3-carboxamide;
N-[5-[5-[cyclohexyl(methyl)carbamoyl]-2-fluorophenyl]-2-[(3R,5S)-3,4,5-trimethylpiperazin-1-yl]phenyl]-6-oxo-4-(trifluoromethyl)-1H-pyridine-3-carboxamide;
N-[5-[2,4-difluoro-3-[[methyl(oxetan-3-yl)amino]methyl]phenyl]-2-[(3R,5S)-3,4,5-trimethylpiperazin-1-yl]phenyl]-6-oxo-4-(trifluoromethyl)-1H-pyridine-3-carboxamide;
N-[5-[2,4-difluoro-5-[[methyl(oxetan-3-yl)amino]methyl]phenyl]-2-[(3R,5S)-3,4,5-trimethylpiperazin-1-yl]phenyl]-6-oxo-4-(trifluoromethyl)-1H-pyridine-3-carboxamide;
N-[5-[3-[(cyclohexylamino)methyl]-2,6-difluorophenyl]-2-[(3R,5S)-3,4,5-trimethylpiperazin-1-yl]phenyl]-6-oxo-4-(trifluoromethyl)-1H-pyridine-3-carboxamide;
N-[5-[4-[(cyclohexylamino)methyl]-2,6-difluorophenyl]-2-[(3R,5S)-3,4,5-trimethylpiperazin-1-yl]phenyl]-6-oxo-4-(trifluoromethyl)-1H-pyridine-3-carboxamide;
N-(4′-carbamoyl-2′-fluoro-4-((3S,5R)-3,4,5-trimethylpiperazin-1-yl)-[1,1′-biphenyl]-3-yl)-6-oxo-4-(trifluoromethyl)-1,6-dihydropyridine-3-carboxamide;
N-(2′-fluoro-4′-morpholino-4-((3S,5R)-3,4,5-trimethylpiperazin-1-yl)-[1,1′-biphenyl]-3-yl)-6-oxo-4-(trifluoromethyl)-1,6-dihydropyridine-3-carboxamide;
N-(5′-carbamoyl-2′-fluoro-4-((3S,5R)-3,4,5-trimethylpiperazin-1-yl)-[1,1′-biphenyl]-3-yl)-6-oxo-4-(trifluoromethyl)-1,6-dihydropyridine-3-carboxamide;
N-(2′,4′-difluoro-5′-((2,4,4-trimethylpentan-2-yl)carbamoyl)-4-((3S,5R)-3,4,5-trimethylpiperazin-1-yl)-[1,1′-biphenyl]-3-yl)-6-oxo-4-(trifluoromethyl)-1,6-dihydropyridine-3-carboxamide;
N-(5′-carbamoyl-2′,4′-difluoro-4-((3S,5R)-3,4,5-trimethylpiperazin-1-yl)-[1,1′-biphenyl]-3-yl)-6-oxo-4-(trifluoromethyl)-1,6-dihydropyridine-3-carboxamide;
N-(2′,3′-difluoro-4′-((2,4,4-trimethylpentan-2-yl)carbamoyl)-4-((3S,5R)-3,4,5-trimethylpiperazin-1-yl)-[1,1′-biphenyl]-3-yl)-6-oxo-4-(trifluoromethyl)-1,6-dihydropyridine-3-carboxamide;
N-(4′-carbamoyl-2′,3′-difluoro-4-((3S,5R)-3,4,5-trimethylpiperazin-1-yl)-[1,1′-biphenyl]-3-yl)-6-oxo-4-(trifluoromethyl)-1,6-dihydropyridine-3-carboxamide; and
N-(5′-(cyclohexylcarbamoyl)-2′-fluoro-4-(3,4,5-trimethylpiperazin-1-yl)-[1,1′-biphenyl]-3-yl)-6-oxo-4-(trifluoromethyl)-1,6-dihydropyridine-3-carboxamide,
or a pharmaceutically acceptable salt thereof.
19. A pharmaceutical composition comprising a pharmaceutically acceptable carrier and/or diluent and a compound of claim 1 , or a pharmaceutically acceptable salt thereof.
20. A method for inhibiting WD repeat domain 5-mixed lineage leukemia 1 protein-protein binding in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of at least one compound of claim 1 , or a pharmaceutically acceptable salt thereof.
21. The method of claim 20 , wherein the subject has a disease selected from the group consisting of bladder cancer, breast cancer, Burkitt's lymphoma, colorectal cancer, gastric cancer, glioma, leukemia, medulloblastoma, MYCN-amplified neuroblastoma, pancreatic cancer, prostate cancer, testicular cancer, and thyroid cancer.
22. A compound of Formula (Ia):
or a pharmaceutically acceptable salt thereof,
wherein:
A 2 is F;
X 8 is CR 26 ;
X 9 is CR 26 ;
R 18 is heterocycloalkyl, optionally substituted with one or more substituents independently selected from the group consisting of halo, C 1-6 alkyl, C 1-6 fluoroalkyl, C 1-6 alkylene-NR 21 R 22 , C 1-6 alkylene-OR 20 , C 1-6 alkylene-SR 20 , NR 21 R 22 , OR 20 , and SR 20 ;
R 19 is selected from the group consisting of:
or a tautomer thereof;
R 20 is H, C 1-6 alkyl, C 1-6 fluoroalkyl, C(O)C 1-6 alkyl, or C(O)C 1-6 fluoroalkyl;
R 21 is H, C 1-6 alkyl, C 1-6 fluoroalkyl, C(O)C 1-6 alkyl, C(O)C 1-6 fluoroalkyl, or heterocycloalkyl;
R 21 is H, C 1-6 alkyl, C 1-6 fluoroalkyl, C(O)C 1-6 alkyl, C(O)C 1-6 fluoroalkyl, or heterocycloalkyl;
R 22 is H, C 1-6 alkyl, C 1-6 fluoroalkyl, C(O)C 1-6 alkyl, C(O)C 1-6 fluoroalkyl, or heterocycloalkyl; or
R 21 and R 22 , together with the nitrogen atom to which they are attached, form a 3-10 membered heterocyclyl, optionally substituted with one or more substituents independently selected from the group consisting of halo, C 1-6 alkyl, C 1-6 fluoroalkyl, C(O)C 1-6 alkyl, C(O)C 1-6 fluoroalkyl, OH, OC 1-6 alkyl, and OC 1-6 fluoroalkyl;
R 24 is H, C 1-6 alkyl, C 1-6 fluoroalkyl, C(O)C 1-6 alkyl, or C(O)C 1-6 fluoroalkyl;
R 25 is H, C 1-6 alkyl, C 1-6 fluoroalkyl, C(O)C 1-6 alkyl, or C(O)C 1-6 fluoroalkyl; or
R 24 and R 25 , together with the nitrogen atom to which they are attached, form a 3-10 membered heterocyclyl, optionally substituted with one or more substituents independently selected from the group consisting of halo, C 1-6 alkyl, C 1-6 fluoroalkyl, OH, OC 1-6 alkyl, and OC 1-6 fluoroalkyl;
each R 26 is independently H, halo, CN, C 1-6 alkyl, C 1-6 fluoroalkyl, C 1-6 alkylene-R 30 , C 1-6 alkylene-NR 28 R 29 , C 1-6 alkylene-OR 27 , C 1-6 alkylene-SR 27 , C(O)NR 28 R 29 , C(O)OR 27 , C(S)NR 28 R 29 , C(S)OR 27 , NR 28 R 29 , OR 27 , OC 1-6 alkylene-R 30 , OC 1-6 alkylene-NR 28 R 29 , OC 1-6 alkylene-OR 27 , OC 1-6 alkylene-SR 27 , SR 27 , SC 1-6 alkylene-R 30 , SC 1-6 alkylene-NR 28 R 29 , SC 1-6 alkylene-OR 27 , SC 1-6 alkylene-SR 27 , or R 30 ;
R 27 is H, C 1-6 alkyl, C 1-6 fluoroalkyl, C 1-6 alkylene-C 3-10 cycloalkyl, C 1-6 alkylene-heterocycloalkyl, C 1-6 alkylene-C 6-10 aryl, C 1-6 alkylene-heteroaryl, C(O)C 1-6 alkyl, C(O)C 1-6 fluoroalkyl, C 3-10 cycloalkyl, heterocycloalkyl, C 6-10 aryl, or heteroaryl, optionally substituted with one or more substituents independently selected from the group consisting of halo, C 1-6 alkyl, C 1-6 alkylene-NR 32 R 33 , C 1-6 alkylene-OR 31 , C 1-6 alkylene-SR 31 , C 1-6 alkylene-C 3-10 cycloalkyl, C 1-6 alkylene-C 6-10 aryl, C 1-6 alkylene-heterocycloalkyl, C 1-6 alkylene-heteroaryl, C 1-6 alkylene-R 31 , C(O)NR 32 R 33 , C(O)OR 31 , C(O)R 31 , NR 32 R 33 , OR 31 , SR 31 , S(O)C 1-6 alkyl, S(O) 2 C 1-6 alkyl, C 3-10 cycloalkyl, heterocycloalkyl, C 6-10 aryl, and heteroaryl;
R 28 is H, C 1-10 alkyl, C 1-10 fluoroalkyl, C 1-6 alkylene-C 3-10 cycloalkyl, C 1-6 alkylene-heterocycloalkyl, C 1-6 alkylene-C 6-10 aryl, C 1-6 alkylene-heteroaryl, C(O)C 1-6 alkyl, C(O)C 1-6 fluoroalkyl, C 3-10 cycloalkyl, heterocycloalkyl, C 6-10 aryl, or heteroaryl, each optionally substituted with one or more substituents independently selected from the group consisting of halo, C 1-6 alkyl, C 1-6 alkylene-NR 32 R 33 , C 1-6 alkylene-OR 31 , C 1-6 alkylene-SR 31 , C 1-6 alkylene-C 3-10 cycloalkyl, C 1-6 alkylene-C 6-10 aryl, C 1-6 alkylene-heterocycloalkyl, C 1-6 alkylene-heteroaryl, C 1-6 alkylene-R 31 , C(O)NR 32 R 33 , C(O)OR 31 , C(O)R 31 , NR 32 R 33 , OR 31 , SR 31 , S(O)C 1-6 alkyl, S(O) 2 C 1-6 alkyl, C 3-10 cycloalkyl, heterocycloalkyl, C 6-10 aryl, and heteroaryl;
R 29 is H, C 1-10 alkyl, C 1-10 fluoroalkyl, C 1-6 alkylene-C 3-10 cycloalkyl, C 1-6 alkylene-heterocycloalkyl, C 1-6 alkylene-C 6-10 aryl, C 1-6 alkylene-heteroaryl, C(O)C 1-6 alkyl, C(O)C 1-6 fluoroalkyl, C 3-10 cycloalkyl, heterocycloalkyl, C 6-10 aryl, or heteroaryl, each optionally substituted with one or more substituents independently selected from the group consisting of halo, C 1-6 alkyl, C 1-6 alkylene-NR 32 R 33 , C 1-6 alkylene-OR 31 , C 1-6 alkylene-SR 31 , C 1-6 alkylene-C 3-10 cycloalkyl, C 1-6 alkylene-C 6-10 aryl, C 1-6 alkylene-heterocycloalkyl, C 1-6 alkylene-heteroaryl, C 1-6 alkylene-R 31 , C(O)NR 32 R 33 , C(O)OR 31 , C(O)R 31 , NR 32 R 33 , OR 31 , SR 31 , S(O)C 1-6 alkyl, S(O) 2 C 1-6 alkyl, C 3-10 cycloalkyl, heterocycloalkyl, C 6-10 aryl, and heteroaryl; or
R 28 and R 29 , together with the nitrogen atom to which they are attached, form a 3-10 membered heterocyclyl, optionally substituted with one or more substituents independently selected from the group consisting of halo, C 1-6 alkyl, C 1-6 alkylene-NR 32 R 33 , C 1-6 alkylene-OR 31 , C 1-6 alkylene-SR 31 , C 1-6 alkylene-C 3-10 cycloalkyl, C 1-6 alkylene-heterocycloalkyl, C 1-6 alkylene-C 6-10 aryl, C 1-6 alkylene-heteroaryl, C 1-6 alkylene-R 31 , C(O)NR 32 R 33 , C(O)OR 31 , C(O)R 31 , NR 32 R 33 , OR 31 , SR 31 , S(O)C 1-6 alkyl, S(O) 2 C 1-6 alkyl, C 3-10 cycloalkyl, heterocycloalkyl, C 6-10 aryl, and heteroaryl;
R 30 is C(O)C 1-6 alkyl, C(O)C 1-6 fluoroalkyl, C 3-10 cycloalkyl, heterocycloalkyl, C 6-10 aryl, or heteroaryl, each optionally substituted with one or more substituents independently selected from the group consisting of halo, C 1-6 alkyl, C 1-6 alkylene-NR 32 R 33 , C 1-6 alkylene-OR 31 , C 1-6 alkylene-SR 31 , C 1-6 alkylene-C 3-10 cycloalkyl, C 1-6 alkylene-heterocycloalkyl, C 1-6 alkylene-C 6-10 aryl, C 1-6 alkylene-heteroaryl, C 1-6 alkylene-R 31 , C(O)R 31 , C(O)OR 31 , C(O)NR 32 R 33 , NR 32 R 33 , OR 31 , SR 31 , S(O)C 1-6 alkyl, S(O) 2 C 1-6 alkyl, C 3-10 cycloalkyl, heterocycloalkyl, C 6-10 aryl, and heteroaryl;
R 31 is H, C 1-6 alkyl, C 1-6 fluoroalkyl, C 1-6 alkylene-C 3-10 cycloalkyl, C 1-6 alkylene-heterocycloalkyl, C 1-6 alkylene-C 6-10 aryl, C(O)C 1-6 alkyl, C(O)C 1-6 fluoroalkyl, C 3-10 cycloalkyl, heterocycloalkyl, or C 6-10 aryl, each optionally substituted with one or more substituents independently selected from the group consisting of halo, C 1-6 alkyl, C 1-6 fluoroalkyl, C 1-6 alkylene-NH 2 , C 1-6 alkylene-NHC 1-6 alkyl, C 1-6 alkylene-N(C 1-6 alkyl)(C 1-6 alkyl), C 1-6 alkylene-OH, C 1-6 alkylene-O—C 1-6 alkyl, C 1-6 alkylene-SH, C 1-6 alkylene-S—C 1-6 alkyl, C 1-6 alkylene-C 3-10 cycloalkyl, C 1-6 alkylene-heterocycloalkyl, C 1-6 alkylene-C 6-10 aryl, C 1-6 alkylene-heteroaryl, C(O)C 1-6 alkyl, C(O)C 1-6 fluoroalkyl, C(O)NH 2 , C(O)NHC 1-6 alkyl, C(O)N(C 1-6 alkyl)(C 1-6 alkyl), C(O)OH, C(O)OC 1-6 alkyl, NH 2 , NHC 1-6 alkyl, N(C 1-6 alkyl)(C 1-6 alkyl), OH, OC 1-6 alkyl, OC 1-6 fluoroalkyl, SH, SC 1-6 alkyl, SC 1-6 fluoroalkyl, S(O)C 1-6 alkyl, S(O) 2 C 1-6 alkyl, C 3-10 cycloalkyl, heterocycloalkyl, C 6-10 aryl, and heteroaryl;
R 32 is H, C 1-10 alkyl, C 1-10 fluoroalkyl, C 1-6 alkylene-C 3-10 cycloalkyl, C 1-6 alkylene-heterocycloalkyl, C 1-6 alkylene-C 6-10 aryl, C(O)C 1-6 alkyl, C 3-10 cycloalkyl, heterocycloalkyl, or C 6-10 aryl, each optionally substituted with one or more substituents independently selected from the group consisting of halo, C 1-6 alkyl, C 1-6 fluoroalkyl, C 1-6 alkylene-NH 2 , C 1-6 alkylene-NHC 1-6 alkyl, C 1-6 alkylene-N(C 1-6 alkyl)(C 1-6 alkyl), C 1-6 alkylene-OH, C 1-6 alkylene-O—C 1-6 alkyl, C 1-6 alkylene-SH, C 1-6 alkylene-S—C 1-6 alkyl, C 1-6 alkylene-C 3-10 cycloalkyl, C 1-6 alkylene-heterocycloalkyl, C 1-6 alkylene-C 6-10 aryl, C 1-6 alkylene-heteroaryl, C(O)C 1-6 alkyl, C(O)C 1-6 fluoroalkyl, C(O)NH 2 , C(O)NHC 1-6 alkyl, C(O)N(C 1-6 alkyl)(C 1-6 alkyl), C(O)OH, C(O)OC 1-6 alkyl, NH 2 , NHC 1-6 alkyl, N(C 1-6 alkyl)(C 1-6 alkyl), OH, OC 1-6 alkyl, OC 1-6 fluoroalkyl, SH, SC 1-6 alkyl, SC 1-6 fluoroalkyl, S(O)C 1-6 alkyl, S(O) 2 C 1-6 alkyl, C 3-10 cycloalkyl, heterocycloalkyl, C 6-10 aryl, and heteroaryl; and
R 33 is H, C 1-10 alkyl, C 1-10 fluoroalkyl, C 1-6 alkylene-C 3-10 cycloalkyl, C 1-6 alkylene-heterocycloalkyl, C 1-6 alkylene-C 6-10 aryl, C(O)C 1-6 alkyl, C 3-10 cycloalkyl, heterocycloalkyl, or C 6-10 aryl, each optionally substituted with one or more substituents independently selected from the group consisting of halo, C 1-6 alkyl, C 1-6 fluoroalkyl, C 1-6 alkylene-NH 2 , C 1-6 alkylene-NHC 1-6 alkyl, C 1-6 alkylene-N(C 1-6 alkyl)(C 1-6 alkyl), C 1-6 alkylene-OH, C 1-6 alkylene-O—C 1-6 alkyl, C 1-6 alkylene-SH, C 1-6 alkylene-S—C 1-6 alkyl, C 1-6 alkylene-C 3-10 cycloalkyl, C 1-6 alkylene-heterocycloalkyl, C 1-6 alkylene-C 6-10 aryl, C 1-6 alkylene-heteroaryl, C(O)C 1-6 alkyl, C(O)C 1-6 fluoroalkyl, C(O)NH 2 , C(O)NHC 1-6 alkyl, C(O)N(C 1-6 alkyl)(C 1-6 alkyl), C(O)OH, C(O)OC 1-6 alkyl, NH 2 , NHC 1-6 alkyl, N(C 1-6 alkyl)(C 1-6 alkyl), OH, OC 1-6 alkyl, OC 1-6 fluoroalkyl, SH, SC 1-6 alkyl, SC 1-6 fluoroalkyl, S(O)C 1-6 alkyl, S(O) 2 C 1-6 alkyl, C 3-10 cycloalkyl, heterocycloalkyl, C 6-10 aryl, and heteroaryl; or
R 32 and R 33 , together with the nitrogen atom to which they are attached, form a 3-10 membered heterocyclyl, optionally substituted with one or more substituents independently selected from the group consisting of halo, C 1-6 alkyl, C 1-6 fluoroalkyl, C 1-6 alkylene-NH 2 , C 1-6 alkylene-NHC 1-6 alkyl, C 1-6 alkylene-N(C 1-6 alkyl)(C 1-6 alkyl), C 1-6 alkylene-OH, C 1-6 alkylene-O—C 1-6 alkyl, C 1-6 alkylene-SH, C 1-6 alkylene-S—C 1-6 alkyl, C 1-6 alkylene-C 3-10 cycloalkyl, C 1-6 alkylene-heterocycloalkyl, C 1-6 alkylene-C 6-10 aryl, C 1-6 alkylene-heteroaryl, C(O)C 1-6 alkyl, C(O)C 1-6 fluoroalkyl, C(O)NH 2 , C(O)NHC 1-6 alkyl, C(O)N(C 1-6 alkyl)(C 1-6 alkyl), C(O)OH, C(O)OC 1-6 alkyl, NH 2 , NHC 1-6 alkyl, N(C 1-6 alkyl)(C 1-6 alkyl), OH, OC 1-6 alkyl, OC 1-6 fluoroalkyl, SH, SC 1-6 alkyl, SC 1-6 fluoroalkyl, S(O)C 1-6 alkyl, S(O) 2 C 1-6 alkyl, C 3-10 cycloalkyl, heterocycloalkyl, C 6-10 aryl, and heteroaryl;
with the proviso that:
(1) R 18 comprises at least one basic nitrogen atom; and
(2) all alkyl and alkylene groups not otherwise specified are optionally substituted with fluoro.
23. A compound of Formula (Ib):
or a pharmaceutically acceptable salt thereof,
wherein:
X 10 is CH;
X 11 is CH;
X 12 is CR 38 ;
X 13 is CH;
R 35 is
R 36 is CHF 2 or CF 3 ;
R 37 is H or CH 3 ;
R 38 is H, halo, CN, C 1-6 alkyl, C 1-6 fluoroalkyl, C 1-6 alkylene-NR 40 R 41 , C 1-6 alkylene-OR 39 , C 1-6 alkylene-SR 39 , C 1-6 alkylene-R 42 , C(O)NR 40 R 41 , C(O)OR 39 , C(S)NR 40 R 41 , C(S)OR 39 , NR 40 R 41 , OC 1-6 alkylene-NR 40 R 41 , OC 1-6 alkylene-OR 39 , OC 1-6 alkylene-SR 39 , OC 1-6 alkylene-R 42 , OR 39 , SC 1-6 alkylene-NR 40 R 41 , SC 1-6 alkylene-OR 39 , SC 1-6 alkylene-SR 39 , SC 1-6 alkylene-R 42 , or SR 39 ;
R 39 is H, C 1-6 alkyl, C 1-6 fluoroalkyl, C 1-6 alkylene-C 3-10 cycloalkyl, C 1-6 alkylene-heterocycloalkyl, C 1-6 alkylene-C 6-10 aryl, C 1-6 alkylene-heteroaryl, C(O)C 1-6 alkyl, C(O)C 1-6 fluoroalkyl, C 3-10 cycloalkyl, heterocycloalkyl, C 6-10 aryl, or heteroaryl, each optionally substituted with one or more substituents independently selected from the group consisting of halo, C 1-6 alkyl, C 1-6 alkylene-NR 44 R 45 , C 1-6 alkylene-OR 43 , C 1-6 alkylene-SR 43 , C 1-6 alkylene-C 3-10 cycloalkyl, C 1-6 alkylene-C 6-10 aryl, C 1-6 alkylene-heterocycloalkyl, C 1-6 alkylene-heteroaryl, C 1-6 alkylene-R 43 , C(O)NR 44 R 45 , C(O)OR 43 , C(O)R 43 , NR 44 R 45 , OR 43 , SR 43 , S(O)C 1-6 alkyl, S(O) 2 C 1-6 alkyl, C 3-10 cycloalkyl, heterocycloalkyl, C 6-10 aryl, and heteroaryl;
R 40 is H, C 1-10 alkyl, C 1-10 fluoroalkyl, C 1-6 alkylene-C 3-10 cycloalkyl, C 1-6 alkylene-heterocycloalkyl, C 1-6 alkylene-C 6-10 aryl, C 1-6 alkylene-heteroaryl, C(O)C 1-6 alkyl, C(O)C 1-6 fluoroalkyl, C 3-10 cycloalkyl, heterocycloalkyl, C 6-10 aryl, or heteroaryl, each optionally substituted with one or more substituents independently selected from the group consisting of halo, C 1-6 alkyl, C 1-6 alkylene-NR 44 R 45 , C 1-6 alkylene-OR 43 , C 1-6 alkylene-SR 43 , C 1-6 alkylene-C 3-10 cycloalkyl, C 1-6 alkylene-C 6-10 aryl, C 1-6 alkylene-heterocycloalkyl, C 1-6 alkylene-heteroaryl, C 1-6 alkylene-R 43 , C(O)NR 44 R 45 , C(O)OR 43 , C(O)R 43 , NR 44 R 45 , OR 43 , SR 43 , S(O)C 1-6 alkyl, S(O) 2 C 1-6 alkyl, C 3-10 cycloalkyl, heterocycloalkyl, C 6-10 aryl, and heteroaryl;
R 41 is H, C 1-10 alkyl, C 1-10 fluoroalkyl, C 1-6 alkylene-C 3-10 cycloalkyl, C 1-6 alkylene-heterocycloalkyl, C 1-6 alkylene-C 6-10 aryl, C 1-6 alkylene-heteroaryl, C(O)C 1-6 alkyl, C(O)C 1-6 fluoroalkyl, C 3-10 cycloalkyl, heterocycloalkyl, C 6-10 aryl, or heteroaryl, each optionally substituted with one or more substituents independently selected from the group consisting of halo, C 1-6 alkyl, C 1-6 alkylene-NR 44 R 45 , C 1-6 alkylene-OR 43 , C 1-6 alkylene-SR 43 , C 1-6 alkylene-C 3-10 cycloalkyl, C 1-6 alkylene-C 6-10 aryl, C 1-6 alkylene-heterocycloalkyl, C 1-6 alkylene-heteroaryl, C 1-6 alkylene-R 43 , C(O)NR 44 R 45 , C(O)OR 43 , C(O)R 43 , NR 44 R 45 , OR 43 , SR 43 , S(O)C 1-6 alkyl, S(O) 2 C 1-6 alkyl, C 3-10 cycloalkyl, heterocycloalkyl, C 6-10 aryl, and heteroaryl; or
R 40 and R 41 , together with the nitrogen atom to which they are attached, form a 3-10 membered heterocyclyl, optionally substituted with one or more substituents independently selected from the group consisting of halo, C 1-6 alkyl, C 1-6 alkylene-NR 44 R 45 , C 1-6 alkylene-OR 43 , C 1-6 alkylene-SR 43 , C 1-6 alkylene-C 3-10 cycloalkyl, C 1-6 alkylene-C 6-10 aryl, C 1-6 alkylene-heterocycloalkyl, C 1-6 alkylene-heteroaryl, C 1-6 alkylene-R 43 , C(O)NR 44 R 45 , C(O)OR 43 , C(O)R 43 , NR 44 R 45 , OR 43 , SR 43 , S(O)C 1-6 alkyl, S(O) 2 C 1-6 alkyl, C 3-10 cycloalkyl, heterocycloalkyl, C 6-10 aryl, and heteroaryl;
R 42 is C(O)C 1-6 alkyl, C(O)C 1-6 fluoroalkyl, C 3-10 cycloalkyl, heterocycloalkyl, C 6-10 aryl, or heteroaryl, each optionally substituted with one or more substituents independently selected from the group consisting of halo, C 1-6 alkyl, C 1-6 alkylene-NR 44 R 45 , C 1-6 alkylene-OR 43 , C 1-6 alkylene-SR 43 , C 1-6 alkylene-C 3-10 cycloalkyl, C 1-6 alkylene-C 6-10 aryl, C 1-6 alkylene-heterocycloalkyl, C 1-6 alkylene-heteroaryl, C 1-6 alkylene-R 43 , C(O)NR 44 R 45 , C(O)OR 43 , C(O)R 43 , NR 44 R 45 , OR 43 , SR 43 , S(O)C 1-6 alkyl, S(O) 2 C 1-6 alkyl, C 3-10 cycloalkyl, heterocycloalkyl, C 6-10 aryl, and heteroaryl;
R 43 is H, C 1-6 alkyl, C 1-6 fluoroalkyl, C 1-6 alkylene-C 3-10 cycloalkyl, C 1-6 alkylene-heterocycloalkyl, C 1-6 alkylene-C 6-10 aryl, C(O)C 1-6 alkyl, C(O)C 1-6 fluoroalkyl, C 3-10 cycloalkyl, heterocycloalkyl, or C 6-10 aryl, each optionally substituted with one or more substituents independently selected from the group consisting of halo, C 1-6 alkyl, C 1-6 fluoroalkyl, C 1-6 alkylene-NH 2 , C 1-6 alkylene-NHC 1-6 alkyl, C 1-6 alkylene-N(C 1-6 alkyl)(C 1-6 alkyl), C 1-6 alkylene-OH, C 1-6 alkylene-O—C 1-6 alkyl, C 1-6 alkylene-SH, C 1-6 alkylene-S—C 1-6 alkyl, C 1-6 alkylene-C 3-10 cycloalkyl, C 1-6 alkylene-heterocycloalkyl, C 1-6 alkylene-C 6-10 aryl, C 1-6 alkylene-heteroaryl, C(O)C 1-6 alkyl, C(O)C 1-6 fluoroalkyl, C(O)NH 2 , C(O)NHC 1-6 alkyl, C(O)N(C 1-6 alkyl)(C 1-6 alkyl), C(O)OH, C(O)OC 1-6 alkyl, NH 2 , NHC 1-6 alkyl, N(C 1-6 alkyl)(C 1-6 alkyl), OH, OC 1-6 alkyl, OC 1-6 fluoroalkyl, SH, SC 1-6 alkyl, SC 1-6 fluoroalkyl, S(O)C 1-6 alkyl, S(O) 2 C 1-6 alkyl, C 3-10 cycloalkyl, heterocycloalkyl, C 6-10 aryl, and heteroaryl;
R 44 is H, C 1-6 alkyl, C 1-6 fluoroalkyl, C 1-6 alkylene-C 3-10 cycloalkyl, C 1-6 alkylene-heterocycloalkyl, C 1-6 alkylene-C 6-10 aryl, C(O)C 1-6 alkyl, C 3-10 cycloalkyl, heterocycloalkyl, or C 6-10 aryl, each optionally substituted with one or more substituents independently selected from the group consisting of halo, C 1-6 alkyl, C 1-6 fluoroalkyl, C 1-6 alkylene-NH 2 , C 1-6 alkylene-NHC 1-6 alkyl, C 1-6 alkylene-N(C 1-6 alkyl)(C 1-6 alkyl), C 1-6 alkylene-OH, C 1-6 alkylene-O—C 1-6 alkyl, C 1-6 alkylene-SH, C 1-6 alkylene-S—C 1-6 alkyl, C 1-6 alkylene-C 3-10 cycloalkyl, C 1-6 alkylene-heterocycloalkyl, C 1-6 alkylene-C 6-10 aryl, C 1-6 alkylene-heteroaryl, C(O)C 1-6 alkyl, C(O)C 1-6 fluoroalkyl, C(O)NH 2 , C(O)NHC 1-6 alkyl, C(O)N(C 1-6 alkyl)(C 1-6 alkyl), C(O)OH, C(O)OC 1-6 alkyl, NH 2 , NHC 1-6 alkyl, N(C 1-6 alkyl)(C 1-6 alkyl), OH, OC 1-6 alkyl, OC 1-6 fluoroalkyl, SH, SC 1-6 alkyl, SC 1-6 fluoroalkyl, S(O)C 1-6 alkyl, S(O) 2 C 1-6 alkyl, C 3-10 cycloalkyl, heterocycloalkyl, C 6-10 aryl, and heteroaryl; and
R 45 is H, C 1-6 alkyl, C 1-6 fluoroalkyl, C 1-6 alkylene-C 3-10 cycloalkyl, C 1-6 alkylene-heterocycloalkyl, C 1-6 alkylene-C 6-10 aryl, C(O)C 1-6 alkyl, C 3-10 cycloalkyl, heterocycloalkyl, or C 6-10 aryl, each optionally substituted with one or more substituents independently selected from the group consisting of halo, C 1-6 alkyl, C 1-6 fluoroalkyl, C 1-6 alkylene-NH 2 , C 1-6 alkylene-NHC 1-6 alkyl, C 1-6 alkylene-N(C 1-6 alkyl)(C 1-6 alkyl), C 1-6 alkylene-OH, C 1-6 alkylene-O—C 1-6 alkyl, C 1-6 alkylene-SH, C 1-6 alkylene-S—C 1-6 alkyl, C 1-6 alkylene-C 3-10 cycloalkyl, C 1-6 alkylene-heterocycloalkyl, C 1-6 alkylene-C 6-10 aryl, C 1-6 alkylene-heteroaryl, C(O)C 1-6 alkyl, C(O)C 1-6 fluoroalkyl, C(O)NH 2 , C(O)NHC 1-6 alkyl, C(O)N(C 1-6 alkyl)(C 1-6 alkyl), C(O)OH, C(O)OC 1-6 alkyl, NH 2 , NHC 1-6 alkyl, N(C 1-6 alkyl)(C 1-6 alkyl), OH, OC 1-6 alkyl, OC 1-6 fluoroalkyl, SH, SC 1-6 alkyl, SC 1-6 fluoroalkyl, S(O)C 1-6 alkyl, S(O) 2 C 1-6 alkyl, C 3-10 cycloalkyl, heterocycloalkyl, C 6-10 aryl, and heteroaryl; or
R 44 and R 45 , together with the nitrogen atom to which they are attached, form a 3-10 membered heterocyclyl, optionally substituted with one or more substituents independently selected from the group consisting of halo, C 1-6 alkyl, C 1-6 fluoroalkyl, C 1-6 alkylene-NH 2 , C 1-6 alkylene-NHC 1-6 alkyl, C 1-6 alkylene-N(C 1-6 alkyl)(C 1-6 alkyl), C 1-6 alkylene-OH, C 1-6 alkylene-O—C 1-6 alkyl, C 1-6 alkylene-SH, C 1-6 alkylene-S—C 1-6 alkyl, C 1-6 alkylene-C 3-10 cycloalkyl, C 1-6 alkylene-heterocycloalkyl, C 1-6 alkylene-C 6-10 aryl, C 1-6 alkylene-heteroaryl, C(O)C 1-6 alkyl, C(O)C 1-6 fluoroalkyl, C(O)NH 2 , C(O)NHC 1-6 alkyl, C(O)N(C 1-6 alkyl)(C 1-6 alkyl), C(O)OH, C(O)OC 1-6 alkyl, NH 2 , NHC 1-6 alkyl, N(C 1-6 alkyl)(C 1-6 alkyl), OH, OC 1-6 alkyl, OC 1-6 fluoroalkyl, SH, SC 1-6 alkyl, SC 1-6 fluoroalkyl, S(O)C 1-6 alkyl, S(O) 2 C 1-6 alkyl, C 3-10 cycloalkyl, heterocycloalkyl, C 6-10 aryl, and heteroaryl;
with the proviso that:
(1) all alkyl and alkylene groups not otherwise specified are optionally substituted with fluoro.Cited by (0)
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